The cerebral cortex is a highly interconnected sheet of neurons that are constantly active and interacting. This ongoing interaction allows context-dependent complex behaviors to be generated by providing a mechanism for the rapid and dynamic modulation of neurdnal responsiveness and flexible coupling of cortical neurons and networks. The generation and impact of cortical-cortical interactions depends upon a precise balance of recurrent excitation and inhibition. In-addition, information processing in the cortex depends critically upon the rate and timing of action potentials. The proposed projects will reveal the functional balance of recurrent excitation and inhibition in vivo and the cellular mechanisms by which the rate and timing of action potential generation is controlled, including during natural sleep and waking. The cortex is built to generate periods of persistent activity, such as during the operation of working memory, or in relation to selective attention. The mechanisms through which persistent, but at the same time rapid, changes in neuronal activity and responsiveness are generated in cortical networks will be investigated. The h-current has proven to be a very important contributor to network activity, through the control of communication between the soma and dendrites of single neurons. The important role of the h-current in persistent activity will be investigated. Finally, the mechanisms by which neuronal network discharge, such as with epileptic seizures, spontaneously stops will be examined with recordings from synaptically connected pairs of neurons. The possibility that synaptic depression or the activation of intrinsic ionic currents contributes to the natural, but temporary, cessation of epileptiform or sleep-related cortical bursts of activity will be examined. These studies will yield valuable information into the basic mechanisms by which cortical networks operate through recurrent excitation and inhibition and how this operation is prevented from being converted into the abnormal discharges of neurological disorders such as epilepsy. PERFORMANCE SITE(S) (organization, city, state). Yale University School of Medicine, New Haven, CT KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name Organization Role on Project David A. McCormick Yale University School of Medicine PI Disclosure Permission Statement. Applicable to SBIR/STTR Only. Seeinstructions. CD Yes . d) No PHS 398 (Rev. 05/01) Page 2 Number pages consecutively at the bottom throughout Form Page 2 the application. Do not use suffixes such as 2a, 2b. Principal Investigator/Program Director (Last, first, middle): McCormick, David A. The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description, Performance Sites, and Personnel.... 2 Table of Contents 3 Detailed Budget for Initial Budget Period (or Modular Budget) 4 Budget for Entire Proposed Period of Support (not applicable with Modular Budget) 5-6 Budgets Pertaining to Consortium/Contractual Arrangements (not applicable with Modular Budget) Biographical Sketch-Principal Investigator/Program Director (Not-to exceed four pages) 7-9 Other Biographical Sketches (Notto exceed four pages for each - See instructions) Resources 10 Research Plan Introduction to Revised Application (Not to exceed 3 pages) Introduction to Supplemental Application (Nottoexceed one page).. A. Specific Aims r*s. [unreadable]-- 11 B. Background and Significance I I. 12-15 C. Preliminary Studies/Progress Report/ [unreadable] ^. (Items A-D: notto exceed 25pages") _^J 15-20 Phase I Progress Report (SBIR/STTR Phase IIONLY) I *SBIR/STTR Phase I: Items A-Dlimitedto 15 pagesj D. Research Design and Methods -*! : .L 20-36 E. Human Subjects Protection of Human Subjects (Required if Item 4 on the Face Page is marked "Yes") Inclusion of Women (Required if Item 4 on the Face Page is marked "Yes") Inclusion of Minorities (Required if Item 4 on the Face Page is marked "Yes") Inclusion of Children (Required if Item 4 on the Face Page is marked "Yes") Data and Safety Monitoring Plan (Required if Item 4 on the Face Page is marked "Yes" and a Phase I, II, or III clinical trial is proposed F. VertebrateAnimals 37-38 G. Literature Cited '. 38-44 H. Consortium/Contractual Arrangements I. Letters of Support (e.g., Consultants) 45 J. Product Development Plan (SBIR/STTR Phase II and Fast-Track ONLY) Checklist 46 Appendix (Five collated sets. No page numbering necessary for Appendix.) , [unreadable] Check if Appendix is Appendices NOTPERMITTED forPhase I SBIR/STTR unless specifically solicited. Included Number of publications and manuscripts accepted for publication (not to exceed 10) Other items (list): PHS 398 (Rev. 05/01) Page 3 Form Page 3